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Monday, November 7, 2011

“Scientists discover gene for autism” (or ovarian cancer, or depression, cocaine addiction, obesity, happiness, height, schizophrenia… and whatever you’re having yourself).These are typical newspaper headlines (all from the last year) and all use the popular shorthand of “a gene for” something.In my view, this phrase is both lazy and deeply misleading and has caused widespread confusion about what genes are and do and about their influences on human traits and disease.

The problem with this phrase stems from the ambiguity in what we mean by a “gene” and what we mean by “for”.These can mean different things at different levels and unfortunately these meanings are easily conflated.First, a gene can be defined in several different ways.From a molecular perspective, it is a segment of DNA that codes for a protein, along with the instructions for when and where and in what amounts this protein should be made.(Some genes encode RNA molecules, rather than proteins, but the general point is the same).The function of the gene on a cellular level is thus to store the information that allows this protein to be made and its production to be regulated.So, you have a gene for haemoglobin and a gene for insulin and a gene for rhodopsin, etc., etc. (around 25,000 such genes in the human genome).The question of what the gene is for then becomes a biochemical question – what does the encoded protein do?

But that is not the only way or probably even the main way that people think about what genes do – it is certainly not how geneticists think about it.The function of a gene is commonly defined (indeed often discovered) by looking at what happens when it is mutated – when the sequence of DNA bases that make up the gene is altered in some way which affects the production or activity of the encoded protein.The visible manifestation of the effect of such a mutation (the phenotype) is usually defined at the organismal level – altered anatomy or physiology or behaviour, or often the presence of disease. From this perspective, the gene is defined as a separable unit of heredity – something that can be passed on from generation to generation that affects a particular trait.This is much closer to the popular concept of a gene, such as a gene for blue eyes or a gene for breast cancer.What this really means is a mutation for blue eyes or a mutation for breast cancer.

The challenge is in relating the function of a gene at a cellular level to the effects of variation in that gene, which are most commonly observed at the organismal level.The function at a cellular level can be defined pretty directly (make protein X) but the effect at the organismal level is much more indirect and context-dependent, involving interaction with many other genes that also contribute to the phenotype in question, often in highly complex and dynamic systems.

If you are talking about a simple trait like blue eyes, then the function of the gene at a molecular level can actually be related to the mutant phenotype fairly easily – the gene encodes an enzyme that makes a brown pigment.When that enzyme is not made or does not work properly, the pigment is not made and the eyes are blue.Easy-peasy.

But what if the phenotype is in some complex physiological trait, or even worse, a psychological or behavioural trait?These traits are often defined at a very superficial level, far removed from the possible molecular origins of individual differences.The neural systems underlying such traits may be incredibly complex – they may break down due to very indirect consequences of mutations in any of a large number of genes.

For example, mutations in the genes encoding two related proteins, neuroligin-3 and neuroligin-4 have been found in patients with autism and there is good evidence that these mutations are responsible for the condition in those patients.Does this make them “genes for autism”?That phrase really makes no sense – the function of these genes is certainly not to cause autism, nor is it to prevent autism.The real link between these genes and autism is extremely indirect.The neuroligin proteins are involved in the formation of synaptic connections between neurons in the developing brain.If they are mutated, then the connections that form between specific types of neurons are altered.This changes the function of local circuits in the brain, affecting their information-processing parameters and changing how different regions of the brain communicate.Ultimately, this impacts on neural systems controlling things like social behaviour, communication and behavioural flexibility, leading to the symptoms that define autism at the behavioural level.

So, mutations in these genes can cause autism, but these are not genes for autism.They are not even usefully or accurately thought of as genes for social behaviour or for cognitive flexibility – they are required, along with the products of thousands of other genes, for those faculties to develop.

But perhaps there are other genetic variants in the population that affect the various traits underlying these faculties – not in such a severe way as to result in a clinical disorder, but enough to cause the observed variation across the general population.It is certainly true that traits like extraversion are moderately heritable – i.e., a fair proportion of the differences between people in this trait are attributable to genetic differences.When someone asks “are there genes for extraversion?”, the answer is yes if they mean “are differences in extraversion partly due to genetic differences?”.If they mean the function of some genetic variant is to make people more or less extroverted, then they have suddenly (often unknowingly) gone from talking about the activity of a gene or the effect of mutation of that gene to considering the utility of a specific variant.

This suggests a deeper meaning – not just that the gene has a function, but that it has a purpose – in biological terms, this means that a particular version of the gene was selected for on the basis of its effect on some trait.This can be applied to the specific sequence of a gene in humans (as distinct from other animals) or to variants within humans (which may be specific to sub-populations or polymorphic within populations).

While geneticists may know what they mean by the shorthand of “genes for” various traits, it is too easily taken in different, unintended ways.In particular, if there are genes “for” something, then many people infer that the something in question is also “for” something.For example, if there are “genes for homosexuality”, the inference is that homosexuality must somehow have been selected for, either currently or under some ancestral conditions.Even sophisticated thinkers like Richard Dawkins fall foul of this confusion – the apparent need to explain why a condition like homosexual orientation persists. Similar arguments are often advanced for depression or schizophrenia or autism – that maybe in ancestral environments, these conditions conferred some kind of selective advantage.That is one supposed explanation for why “genes for schizophrenia or autism” persist in the population.

Natural selection is a powerful force but that does not mean every genetic variation we see in humans was selected for, nor does it mean every condition affecting human psychology confers some selective advantage.In fact, mutations like those in the neuroligin genes are rapidly selected against in the population, due to the much lower average number of offspring of people carrying them.The problem is that new ones keep arising – in those genes and in thousands of other required to build the brain.By analogy, it is not beneficial for my car to break down – this fact does not require some teleological explanation.Breaking down occasionally in various ways is not a design feature – it is just that highly complex systems bring an associated higher risk due to possible failure of so many components.

So, just because the conditions persist at some level does not mean that the individual variants causing them do.Most of the mutations causing disease are probably very recent and will be rapidly selected against – they are not “for” anything.